Pulmonary hypertension (PH) is a disorder characterized by abnormally elevated pulmonary artery (PA) pressures. PH associated with chronic obstructive pulmonary disease (COPD) affects a significant number of patients and is associated with worsened lung function decline, increased frequency of exacerbations, and increased mortality. There are currently no therapies available for treatment of COPD-associated PH and thus new pathways and therapeutic targets are needed to address this critical need. Recent work in our laboratory has identified acetyl-proline-glycine-proline (AcPGP), the end result of cigarette- smoke induced collagen destruction, as a key marker for COPD pathogenesis. PGP acts on inflammatory cells through CXC receptors (CXCR1/2). Signaling through this CXCR2 receptor has been implicated in the development of PH. As an extension, the hypothesis that AcPGP mediates pulmonary vascular endothelial cell dysfunction and serves as a risk factor for the development of PH in COPD will be tested through the following independent but inter-related aims: 1. Study the phenotype and mechanism of COPD-associated PH in murine models of exogenous AcPGP administration 2. Determine the role of the neutrophil and CXCR1/2 in AcPGP mediated pulmonary vascular remodeling 3. Investigate the predictive value of AcPGP levels in the development of pulmonary vascular disease detected by CT in a cohort of COPD patients This project explores new concepts in the pathobiology of COPD-associated PH through PA endothelial cells, a novel animal model of disease, and translates these findings into human disease. This career development plan and the research aims as outlined above are of equal importance. Combined with a strong mentoring committee, additional training in immunology, metabolism, cardiopulmonary physiology, study design, methodology, and statistical analysis will meet Dr. Wells' specific educational needs as a budding academician. The opportunities created by this career development award will result in the creation of a physician-scientist with the skills necessary to accurately and ethically answer important scientific questions related to COPD-associated PH, successfully obtain future independent funding, and make important differences in the lives of patients affected with these devastating illnesses.